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DIALOGUES in DIABETES VINDICO medical education Supplement to December 2013 Cardiovascular Benefits of Glycemic Control: The Potential Role of Incretin Therapeutics Volume 3 • Number 4 • DECEMBER 2013

Transcript of DIALOGUES in DIABETES - The Doctor's Channel · DIALOGUES in DIABETES VINDICO medical education...

Page 1: DIALOGUES in DIABETES - The Doctor's Channel · DIALOGUES in DIABETES VINDICO medical education Supplement to December 2013 Cardiovascular Benefits of Glycemic Control: The Potential

DIALOGUES in DIABETES

VINDICOmedical education

Supplement to

December 2013

Cardiovascular Benefits of Glycemic Control: The Potential Role of Incretin Therapeutics

Volume 3 • Number 4 • DECEMBER 2013

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Featured articles introductionReducing cardiovascular risk in patients with diabetes remains an

ever challenging problem. Recent clinical trials have raised into question the value of glycemic control in reducing cardiovascular risk in this patient population, emphasizing a more comprehensive approach including lipid, hypertension, and glucose regulation.

Recent advances in incretin-based therapies have provided us with a valu-able weapon in fighting the battle to reduce cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). The incretin pathway is responsible for both insulin and glucagon regulation. The injectable glucagon-like peptide-1 (GLP-1) receptor agonists mimic the effects of endogenous GLP-1, which stimulates pancreatic insulin secretion in a glucose-dependent fashion, suppressing pan-creatic glucagon output, slowing gastric emptying, and decreasing appetite. This action induces weight loss, which can be significant in some patients. The oral dipeptidyl peptidase-4 (DPP-4) inhibitors enhance circulating concen-trations of active GLP-1 agonists by suppressing the inactivation of GLP-1 agonists by DPP-4 inhibitors. Their major effect appears to be in the regulation of insulin and glucagon secretion, as well as being weight neutral. Also of clini-cal interest is the impact of incretin-based therapies on plasma lipids as well as their cardiovascular effects and impact on cardiovascular risk.

This issue of Dialogues in Diabetes will explore several important clinical issues: (1) reducing cardiovascular disease risk in patients with T2DM; (2) the cardiovascular benefits of glycemic control with updates on the use of anti-diabetic medications for the prevention of cardiovascular events; and (3) the effects of incretin-based therapies on inflammatory markers and cardiovascular risk.

I would like to thank the faculty for their invaluable contribution to this issue and trust that this CME publication will assist you in managing your patients with this challenging disease.

Michael H. Davidson, MD, FACC, FACP, FNLA

Michael H. Davidson, MD, FACC, FACP, FNLAProfessor, Director of the Lipid ClinicThe University of Chicago, Pritzker School of MedicineChicago, IL

Robert J. Chilton, MD, DO, FACC, FAHA, FACPProfessor of Medicine Division of CardiologyThe University of Texas Health Science Center at San AntonioSan Antonio, TX

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESCProfessor of Medicine, Harvard Medical SchoolExecutive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart and Vascular CenterBoston, MA

4 Addressing Challenges of Reducing CVD Risk in Patients with Type 2 Diabetes Mellitus

8 Cardiovascular Benefits of Glycemic Control

12 Evaluation of Cardiovascular Effects of Incretin Therapy for Type 2 Diabetes Mellitus

16 Case Presentation: Reducing CVD Risk in Patients

with T2DM: Utilizing Incretin Therapeutics

18 CME Instructions and CME Posttest

19 CME Registration Form

EARN CME CREDIT

This activity is supported by an educational grant from

VINDICOmedical education

This continuing medical education activity is sponsored by

learning objectivesAt the conclusion of this series, participants should be able to:

• Assess the pathophysiology of hyperglycemia, its role in macrovascular and microvascular diseases, and the role of incretin pathways in type 2 diabetes mellitus.

• Examine the differences in mechanism of action, efficacy, and safety of treatment options that target the incretin pathway.

• Examine approaches to managing the obese patient with type 2 diabetes.

• Incorporate evidence-based guidelines and recommendations into practice when considering the use of incretin-based therapies for type 2 diabetes.

• Utilize GLP-1 agonists and DPP-4 inhibitors in combination with insulin and oral agents to achieve optimal glycemic control.

• Analyze the potential cardiovascular benefits of incretin therapies in addition to glycemic control.

2 Volume 3 • Number 4 • DECEMBER 2013 | Dialogues in Diabetes

DIALOGUES in DIABETES

Volume 3 • Number 4 • DECEMBER 2013

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Medical DirectorRonald Codario, MD, FACP, FNLA, CCMEP

Vice President, Office of Medical AffairsJames T. Magrann

Director of Medical EducationChris Rosenberg

Medical EditorSharon Powell

Scientific DirectorJennifer Frederick, PharmD, BCPS

Program ManagerKristin Riday

Publication DesignKimi Dolan

David BarkerTheresa McIntire

vindico Medical education

Created and published by Vindico Medical Education, 6900 Grove Road, Building 100, Thorofare, NJ 08086-9447. Telephone: 856-994-9400; Fax: 856-384-6680. Printed in the USA. Copyright © 2013. Vindico Medical Education. All rights reserved. No part of this publication may be reproduced without written permission from the publisher. The material presented at or in any of Vindico Medical Education continuing medical education activities does not necessarily reflect the views and opinions of Vindico Medical Education. Neither Vindico Medical Education nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product.

AccreditationVindico Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit DesignationVindico Medical Education designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This enduring material is approved for 1 year from the date of original release, December 1, 2013 to December 1, 2014.

How To Participate in this Activity and Obtain CME CreditTo participate in this CME activity, you must read the objectives and articles, complete the CME posttest, and fill in the evaluation. Provide only one (1) correct answer for each question. A satisfactory score is defined as answering 70% of the posttest questions correctly. Upon receipt of the completed materials, if a satisfactory score on the posttest is achieved, Vindico Medical Education will issue an AMA PRA Category 1 Credit(s)™ certificate.

ReviewersRonald A. Codario, MD, FACP, FNLA, CCMEPCarol H. Wysham, MD

DisclosuresIn accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support, all CME providers are required to disclose to the activity audience the relevant financial relationships of the planners, teachers, and authors involved in the development of CME content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CME activity content over which the individual has control.

The authors disclose that they do have significant financial interests in any products or class of products discussed directly or indirectly in this activity, including research support.

Planning Committee and Faculty members report the following relationship(s):

Lawrence Blonde, MD, FACP, FACEResearch Grant Support: To Ochsner for his role as investigator from Eli Lilly and Company, Novo Nordisk, and Sanofi-AventisSpeaker’s Bureau: Amylin Pharmaceuticals, Inc., Bristol-Myers Squibb/AstraZeneca, Janssen Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, L.L.C., Merck & Co. Inc., Novo Nordisk, Sanofi-Aventis, Santarus, Vivus, Inc.Consultant: Amylin Pharmaceuticals, Inc., Eisai Inc, GlaxoSmithKline, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer, Sanofi-Aventis, Santarus

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESCContracted Research: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company

Robert Chilton, MD, DO, FACC, FAHA, FACPConsulting Fees: Bristol-Myers Squibb, Lilly, MSD, Takeda

Michael H. Davidson, MD, FACC, FACP, FNLAConsulting Fees: AbbVie, Amgen, AstraZeneca, Daiichi-Sankyo, Esperion, Lipidemx, Merck & Co., IncSpeakers Bureau: Merck & Co., Inc.Ownership Interest: Prior to July 2013, ownership interest in Omthera Pharmaceuticals, Inc.

Ralph A. DeFronzo, MDConsulting Fees: Amylin, Bristol-Myers Squibb, Janssen, Lexicon, Novo Nordisk, TakedaContracted Research: Amylin, Bristol-Myers Squibb, Lexicon, TakedaSpeakers Bureau: Amylin, AstraZeneca, Bristol-Myers Squibb, Janssen, Novo Nordisk

Vivian A. Fonseca, MD, FRCPHonoraria for Consulting Fees and Lectures: Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Novo Nordisk, PamLabs, Sanofi-Aventis, TakedaResearch Support (to Tulane): Abbott, Eli Lilly, Endo Barrier, Novo Nordisk, Pan American Laboratories, Rcata, Sanofi-Aventis

Robert R. Henry, MD Grant/Research Support: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Sanofi-AventisConsultant: Boehringer Ingelheim, Intarcia, Isis, Eli Lilly, Novo Nordisk, Roche/Genentech, Sanofi-AventisAdvisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Elcelyx, Eli Lilly, Intarcia, Johnson & Johnson/Janssen, Merck, Novo Nordisk, Roche/Genentech, Sanofi-Aventis

Reviewers report the following relationship(s):

Ronald A. Codario, MD, FACP, FNLA, CCMEPNo relevant financial relationships to disclose.

Carol H. Wysham, MDConsulting Fees: Boehringer Ingelheim, Eli Lilly, Janssen, Sanofi-AventisSpeaker’s Bureau: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Medtronic, Novo Nordisk, Sanofi-AventisContract Research: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Merck & Co., Inc., Novo Nordisk, Sanofi-Aventis

Vindico Medical Education staff report the following relationship(s):

No relevant financial relationships to disclose.

Signed disclosures are on file at Vindico Medical Education, Office of Medical Affairs and Compliance.

Target Audience The intended audience for this activity is endocrinologists and other health care professionals involved in the treatment of patients with type 2 diabetes.

Unlabeled and Investigational UsageThe audience is advised that this continuing medical education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage. All activity participants will be informed if any speakers/authors intend to discuss either non-FDA approved or investigational use of products/devices.

chieF Medical editorRobert R. Henry, MDProfessor of Medicine

Division of Endocrinology & MetabolismUniversity of California, San Diego

Chief, Section of Diabetes, Endocrinology and MetabolismDirector, Center for Metabolic Research

VA San Diego Healthcare SystemSan Diego, CA

editorial boardLawrence Blonde, MD, FACP, FACE

Director, Ochsner Diabetes Clinical Research UnitDepartment of Endocrinology

Ochsner Medical CenterNew Orleans, LA

Michael H. Davidson, MD, FACC, FACP, FNLAProfessor, Director of the Lipid Clinic

The University of Chicago, Pritzker School of MedicineChicago, IL

Ralph A. DeFronzo, MDProfessor of Medicine

Chief, Diabetes DivisionUniversity of Texas Health Science Center of San Antonio

Deputy DirectorTexas Diabetes Institute

San Antonio, TX

Vivian A. Fonseca, MD, FRCPProfessor of Medicine and Pharmacology Tullis–Tulane Alumni Chair in Diabetes

Chief, Section of EndocrinologyTulane University Health Sciences Center

New Orleans, LA

contributing FacultyDeepak L. Bhatt, MD, MPH, FACC,

FAHA, FSCAI, FESCProfessor of Medicine, Harvard Medical School

Executive Director of Interventional Cardiovascular Programs,Brigham and Women’s Hospital Heart and Vascular Center

Boston, MA

Robert Chilton, MD, DO, FACC, FAHA, FACPProfessor of Medicine Division of Cardiology

The University of Texas Health Science Center at San AntonioSan Antonio, TX

3Volume 3 • Number 4 • DECEMBER 2013 | Dialogues in Diabetes

DIALOGUES in DIABETES

Volume 3 • Number 4 • DECEMBER 2013

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Addressing Challenges of Reducing CVD Risk in Patients with Type 2 Diabetes Mellitus Michael H. Davidson, MD, FACC, FACP, FNLA

The leading cause of death for patients with type 2 diabetes mellitus (T2DM) is cardiovas-

cular disease (CVD), and once a patient with T2DM has a cardiovascular event, long-term survival is significantly re-duced. Therefore, in the field of preven-tive cardiology, there is intensive focus to modify cardiovascular risk factors in a patient with T2DM before the initial event. Although patients with T2DM without coronary artery disease (CAD) have a 10-year risk of future events that is lower than patients with CAD, in the latest population studies, their lifetime risk of cardiovascular events is >50%,

and the new American Heart Associa-tion/American College of Cardiology (AHA/ACC) 2013 Guidelines recom-mends high-intensity statin therapy for those >40 years of age with risk fac-tors to achieve low-density lipoprotein cholesterol/non-high-density lipopro-tein cholesterol (LDL-C/non-HDL-C) reduction.1 The importance of giving a maximally tolerated statin with high intensity received primary emphasis

because it most accurately reflects the data that statins reduce the relative risk of atherosclerotic cardiovascular disease (ASCVD) events similarly in patients with and without diabetes and in primary and secondary preven-tion in those with diabetes, along with evidence that high-intensity statins re-duce ASCVD risk more than moder-ate-intensity statins. Because patients with diabetes often have lower LDL–C levels than patients without diabetes, “goal” directed therapy often encour-ages the use of a lower statin dose, and non-statin drugs may be added on to address low HDL–C or high triglycer-ides, for which randomized control trial evidence of an ASCVD risk reduction benefit is lacking.1 However, expert opinion guidelines, such as those de-veloped by the American Association of Clinical Endocrinologists (AACE) continue to recommend combination therapy for the achievement of target goals for LDL-C/non-HDL-C and po-tentially low-density lipoproteins parti-cles (LDL-P), apolipoprotein B (apoB), and triglycerides.2 Once a patient with T2DM is diagnosed with CAD, sec-ondary prevention strategies may still be effective, but improved survival has been difficult to demonstrate with more intensive glycemic control.3,4 A consensus is developing that although microvascular benefits can be demon-strated with more intensive glycemic control, macrovascular benefits of the existing therapies to improve out-comes has not yet been proven in large

randomized clinical trials. This has led to the evaluation of the effects of spe-cific hypoglycemic agents on tradition-al cardiovascular risk factors, such as lipoproteins, blood pressure, and body weight, as well as the potential adverse effects of these therapeutic agents on cardiovascular safety. Therefore, each pharmaceutical agent that is used to improve glycemic control should also be evaluated in the context of global cardiovascular risk reduction and even-tually have outcome benefits demon-strated in large randomized trials.

In patients with T2DM, the thera-peutic approach should include diet control, physical exercise, smoking cessation, and particularly, pharma-cologic interventions including anti-dyslipidemics (mainly statins) and hypoglycemic agents.

Evidence for the benefits of lipid-lowering therapy in patients with T2DM has been demonstrated in multiple clinical trials, and it is well acknowledged that patients with T2DM have an increased prevalence of lipid abnormalities contributing to their high risk of CVD. In patients with diabetes, there is overproduc-tion of very-low-density lipoprotein (VLDL), mediated by an increased influx of free fatty acids into the liver. In the setting of hepatic insu-lin resistance, VLDL secreted by the liver has an increased triglycer-ide content and apolipoprotein CIII (apoCIII) synthesis is upregulated, leading to competition for apoE

It is well acknowledged that

patients with T2DM have an

increased prevalence of lipid

abnormalities contributing to their

high risk of cardiovascular disease.

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receptor clearance of atherogenic remnant lipoproteins and decreased lipolysis. Increased hepatic secre-tion of enlarged VLDL with apoCIII results in impaired conversion of VLDL to low-density lipoprotein (LDL). Triglyceride within VLDL is transferred into LDL and high densi-ty lipoprotein (HDL) in exchange for cholesterol ester by cholesteryl ester transfer protein. After lipolysis by hepatic lipases, LDL and HDL sizes are significantly reduced. Therefore the net result of hepatic insulin resis-tance is increased VLDL secretion, an abundance of small dense LDL, and very low HDL-C, the hallmark features of the dyslipidemia associ-ated with T2DM. In addition, due to impaired lipolysis of VLDL, com-petition develops for clearance of dietary fat, resulting in markedly en-hanced postprandial lipemia. All of these factors result in increased CV risk in patients with T2DM.5

The Role of Incretin Therapeutics

Dipeptidyl peptidase-4 (DPP-4) in-hibitors have little effect on fasting lipid profiles. Although, DPP–4 inhibitors have been reported to reduce total cho-lesterol, results are inconsistent across trials. A recent meta-analysis of 17 clinical trials with a variety of DPP-4 inhibitors demonstrated approximately

a 6 mg/dL reduction in total cholesterol compared with controls.6

However, DPP-4 inhibitors ap-pear to have a significant beneficial effect on postprandial lipemia. Sita-gliptin was shown to reduce the area under the curve for triglycerides and apolipoprotein B-48, as well as apoli-poprotein B-100.7 This suggests that DPP-4 inhibitors decrease postpran-dial plasma levels of triglyceride-rich lipoproteins of both intestinal and he-patic origin. Similar effects on post-prandial lipemia have been demon-strated with other DPP-4 inhibitors, such as vildagliptin and alogliptin.8

GLP-1 is a hormone that normally promotes the production and secre-tion of insulin from pancreatic islet-cells in a glucose-dependent manner, reduces hepatic glucose production, minimizes the release of glucagon from pancreatic islet cells, and slows gastric emptying and induces satiety, thereby promoting weight loss. Fail-ure of secretion of the incretin hor-mone GLP-1 plays a prominent role in T2DM, and restoration of GLP-1 action is an important therapeutic objective. GLP-1 receptor agonists have also been identified in the heart, kidneys, and blood vessels, leading

Table. Effect of GLP-1 Agonists on Lipids

Parameter Liraglutide Rosiglitazone Glimepiride Glargine Exenatide Placebo

TC (mmol/L) -5.07 11.31 -1.95 0.78 -1.95 0.39

LDL-C (mmol/L) -7.8 2.34 -4.68 -2.73 -5.85 -5.07

VLDL (mmol/L) 3.9 8.58 4.68 4.68 6.24 6.24

HDL-C (mmol/L) -1.56 0.78 1.56 1.56 1.95 -1.59

FFA (mmol/L) -2.34 N/A -1.33 N/A -0.8 -1.59

TG (mmol/L) -17.8 -4.45 -14.24 -13.35 -4.45 1.78

Source: Plutzky J, et al. Diabetologia. 2009;52(Suppl 1):S299-S300.

There has been speculation that GLP-1 receptor agonists may reduce markers of CVD risk.Source: Ban K, et al. Circulation. 2008;117(18):2340-2350. Reprinted with permission from Wolters Kluwer Health.

Figure 1. Location of GLP-1 Receptors in the Cardiovascular System

5Volume 3 • Number 4 • DECEMBER 2013 | Dialogues in Diabetes

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to the hypothesis that GLP-1 receptor agonists may reduce markers of CVD risk (Figure 1, see page 5).9 GLP-1 receptor agonists appear to have the greatest effects on triglyceride-rich lipoproteins compared with other hypoglycemic agents, potentially because of their beneficial effects on

body weight. GLP-1 receptor ago-nists lower levels of total cholesterol by 5% (Table, see page 5).6 The ef-fect of the GLP-1 receptor agonists, liraglutide and exenatide on reducing

postprandial lipemia, has also been established with respect to the sup-pression of postprandial elevations in lipids and lipoproteins (Figure 2).10

Recent CV Safety Trials with Incretin Therapies

Saxagliptin Assessment of Vascu-lar Outcomes Recorded in Patients with Diabetes Mellitus–Thromboly-sis in Myocardial Infarction 53 (SA-VOR-TIMI 53) randomized 16,492 patients with T2DM and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo. The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 pa-tients randomized to receive placebo (7.3% and 7.2%, respectively) at a median followup of 2.1 years. A ma-jor secondary endpoint, a composite of cardiovascular death, myocardial

infarction, stroke, hospitalization for unstable angina, coronary revas-cularization, or heart failure, also occurred at similar rates in the treat-ment and placebo groups (12.8% and 12.4%, respectively). However, more patients in the treatment group than in the placebo group were hos-pitalized for heart failure (3.5% vs. 2.8%). The etiology of the excess risk of heart failure is uncertain.11

Similarly, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial with another DPP-4 inhibitor, alogliptin, with pa-tients with T2DM and a recent acute myocardial infarction or unstable angina requiring hospitalization showed that the primary endpoint, a composite of death from cardiovas-cular causes, nonfatal myocardial infarction, or nonfatal stroke, did not occur significantly more often at a median followup of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 pa-tients randomized to receive placebo (11.3% vs. 11.8%, respectively). For both studies, it was reassuring that there was not an increase in pan-creatitis or pancreatic cancer in the patients treated with a DPP-4 inhibi-tor compared to control. The find-ings from the SAVOR and EXAM-INE trials demonstrate that DPP-4 inhibition with either saxagliptin or alogliptin neither increases nor de-creases the rate of ischemic events over a median 2-year period, al-though longer duration of treatment may have resulted in a different out-come. Without significant changes in lipid levels or blood pressure it was unlikely that a very modest dif-ference in A1C would have resulted in a cardiovascular benefit after such a short treatment period.12

There are currently 3 large, ran-domized controlled trials investigating cardiovascular outcomes in patients with T2DM with GLP-1 therapies.

5(A)

4

3

2

2 4 6 80Hours after meal

Drug: P=0.0001Drug Time: P=0.0001

Seru

m T

G(m

mol

/L)

* *

*

Exenatide Placebo

4(C)

3

2

1

2 4 6 80

0

Hours after meal

Drug: P=0.0001Drug Time: P=0.001

Pla

sma

RLP

-TG

(mm

ol/

L)

††

* **

0.7(D)

0.6

0.5

0.4

0.3

2 4 6 800.2

Hours after meal

Drug: P=0.0001Drug Time: P=0.0008

Pla

sma

RLP

-C(m

mo

l/L)

† †

*

16(B)

14

12

10

6

8

2 4 6 804

Hours after meal

Drug: P=0.0003Drug Time: P=0.008

Seru

m A

po

B48

(mg

/L)

††

**

*

TriglyceridesP <.001

35 Subjects: IGT (20) or Type 2 DM (15)Single Injection: Exenatide or PlaceboFollowed by High Fat Meal (5384 KJ)

RemnantLipoprotein

TriglyceridesP <.001

RemnantLipoproteinCholesterol

P <.001

Apo-B48P <.001

Liraglutide and exenatide suppresses postprandial elevations in lipids and proteins.Source: Reprinted from Schwartz EA, et al. Atherosclerosis. 2010;212(1):217-222 with permission from Elsevier.

Figure 2. Exenatide and Postprandial Lipemia

Findings from the SAVOR and

EXAMINE trials demonstrate that

DPP-4 inhibition with either

saxagliptin or alogliptin neither

increases nor decreases the rate

of ischemic events over a median

2-year period.

6 Volume 3 • Number 4 • DECEMBER 2013 | Dialogues in Diabetes

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The Exenatide Study of Cardiovascu-lar Event Lowering (EXSCEL) trial is an ongoing multicenter trial random-izing more than 9,500 patients with T2DM on stable doses of oral glu-cose-lowering agents to once-weekly exenatide injections or placebo with a followup of 4 years for major mac-rovascular events. The Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treat-ment With AVE0010 (Lixisenatide) (ELIXA) trial is another ongoing multicenter trial that will random-ize an estimated 6,000 patients with T2DM to lixisenatide or placebo after ACS and followup for major cardio-vascular events. Finally, the Liraglu-tide Effect and Action in Diabetes: Evaluation of Cardiovascular Out-come Results—A Long Term Evalua-tion (LEADER) trial has randomized 9,341 patients with hemoglobin A1C levels >7% to receive liraglutide or placebo and will followup for major cardiovascular events until 2016.13

The GLP-1 receptor agonists are a promising class of glucose-lower-ing agents given their weight-loss properties and the improvements in surrogates, such as blood pres-sure and cholesterol. These trials are therefore more likely to demonstrate

a CV outcome benefit if the improve-ment in weight loss induced risk fac-tors can be sustained over the length of the multiple years of the studies.

ConclusionEvidence-based approaches for

reducing cardiovascular risk in pa-tients with diabetes include statins regardless of baseline LDL-C. There-fore the new AHA/ACC Guidelines are now consistent with the ADA Guidelines which recommends high-intensity statin therapy for those >40 years of age with risk factors. In re-gards to the selection of the most ap-propriate drug to add to metformin to reduce A1C, DPP-4 inhibitor-based therapies provide an option that have demonstrated safety but as of yet have not been shown to re-duce CV events despite the promise of some of the earlier clinical trials. However, the SAVOR and EXAM-INE outcome trials with saxagliptin and alogliptin respectively may have been too short of treatment duration and/or with insufficient differences in A1C and other cardiovascular risk factor effects to result in a clinically meaningful benefit. The GLP-1 re-ceptor agonists provide an additional improvement in risk factor reduction, such as lower fasting triglycerides,

increases in HDL-C, and reduced blood pressure (which may be weight loss mediated) and therefore still hold out promise for cardiovascular event reduction in the high-risk patient with diabetes population.

References1. Stone NJ, et al. J Am Coll Cardiol.

2013;pii:S0735-1097(13)06028-2. [Epub ahead of print]

2. Garber AJ, et al. Endocr Pract. 2013; 19(2):327-336.

3. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977-986.

4. Stratton IM, et al. BMJ. 2000; 321(7258):405-412.

5. David MH. Am J Cardiol. 2012;110(9 Suppl):43B-49B.

6. Plutzky J, et al. Diabetologia. 2009; 52(Suppl 1):A762-P.

7. Tremblay AJ, et al. Diabetes Obes Metab. 2011;13(4):366–373.

8. Matikainen N, et al. Diabetologia. 2006; 49(9):2049–2057.

9. Ban K, et al. Circulation. 2008;117(18): 2340-2350.

10. Schwartz EA, et al. Atherosclerosis. 2010;212(1):217–222.

11. Scirica BM, et al. N Engl J Med. 2013; 369(14):1317-1326.

12. White WB, et al. N Engl J Med. 2013; 369(14):1327-1335.

13. Marso SP, et al. Am Heart J. 2013; 166(5):823-830.

Full references are available at www.healio.com/endocrinology/education-lab.

7Volume 3 • Number 4 • DECEMBER 2013 | Dialogues in Diabetes

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Patients with type 2 diabetes mellitus (T2DM) are at a 2-fold to 4-fold increased risk

for cardiovascular disease (CVD) and mortality.1 Commonly, T2DM clus-ters with other major cardiovascular risks such as dyslipidemia, obesity, and hypertension. Despite advances in current armamentarium for the treatment of T2DM, half of patients with T2DM still fail to reach the goal of A1C <7%,2 and even fewer attain the more rigid goal of <6.5%. Fewer patients (18.8%) achieve all three ABCs (A1C, blood pressure, and cholesterol) goals. The importance of tight glycemic control in T2DM

to reduce the risk of microvascular diseases has been well established,3 while the impact on macrovascular disease is still a matter of debate.

HyperglycemiaExperimental work has shown

repeatedly that a hyperglycemic mi-lieu bolsters multiple mechanisms to accelerate atherosclerosis. Hyper-glycemia is associated with endothe-lial dysfunction, impaired fibrinoly-sis, increased platelets aggregation,

dysfunctional arterial remodeling, oxidative stress, and increased pro-duction of advanced glycosylation end products. The belief that low-ering glucose is inextricably linked to a reduction in cardiovascular morbidity and mortality was re-cently challenged by observational findings that rosiglitazone-treated patients were at increased risk for acute myocardial infarction (MI). This led to the 2008 FDA guidance which required all new glucose low-ering agents to conduct large cardio-vascular safety trials. Additionally, large randomized controlled trials evaluating the effect of tight glyce-mic control on cardiovascular event rates in people with T2DM4,5,6,7,8 all failed to show a cardiovascular ben-efit of the intensive glucose manage-ment. There are several caveats to interpreting the results of the trials: (1) pharmacotherapeutic interven-tions; (2) the patient population studied (especially with respect to age, duration of diabetes, and preex-isting CVD); (3) the baseline A1C; (4) the glycemic goals; and (5) du-ration of followup. Evidence from these studies confirm that intensive approach to glucose control (us-ing older agents) invariably results in higher risk of hypoglycemia and weight gain which may mask the fa-vorable effects of glucose lowering on the cardiovascular system.

Incretin-based TherapiesThe availability of the incretin-

based therapies dipeptidyl pepti-dase-4 (DPP-4) inhibitors and gluca-gon-like peptide-1 (GLP-1) receptor

agonists raised the hope that while the older agents had failed to alter the course of cardiovascular dis-ease, the incretins could potentially modify the disease process. The gly-cemic control of the incretin-based agents is comparable to other anti-diabetic agents but is achieved with-out weight gain (DPP-4 inhibitor) or even weight loss (GLP-1 receptor agonist) and with a low risk of hy-poglycemia. Furthermore, incretin-based agents have demonstrated in clinical trials beneficial effects on several well-known cardiovascular biomarkers (Table 1).

DPP-4 is a widely expressed protease and has been localized on the kidney, small intestine, liver, and heart tissue.9 In clinical trials, DPP-4 inhibitors result in a mean decrease in A1C ranging from 0.3% to 1%,10 are weight neutral with no increased risk of hypoglycemia unless combined with insulin or sulfonylureas, show modest reduc-tion in systolic blood pressure,11,12 improve postprandial lipids,13 and result in favorable changes in endo-thelial cell function and markers of inflammation. The potential cardio-vascular protective role of DPP-4 inhibitors potentially involves both GLP-1 dependent and independent mechanisms. Overall, the knowl-edge about the effect of this class on cardiac structure and function is limited to experimental models. Only small clinical studies of short duration, mostly assessing cardio-vascular biomarkers, exist. The ma-jority of the evidence regarding the cardiovascular impact of incretin-

Cardiovascular Benefits of Glycemic ControlRobert J. Chilton, MD, DO, FACC, FAHA, FACP

The glycemic control of the

incretin-based agents is

comparable to other antidiabetic

agents but without the weight

gain and weight loss and with a

low risk of hypoglycemia.

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based therapies is derived from ad-ministering native GLP-1 receptor agonists or its analogs.

GLP-1 receptor agonists are widely expressed in the human heart and are found in cardiomyo-cytes, endocardium, and coronary endothelium.14 In clinical trials, when compared with DPP-4 in-hibitors, GLP-1 receptor agonists result in more robust A1C reduc-tion in weight loss, blood pressure, and lipids improvement. Depending on background glucose-lowering therapy, a weight loss of 1 to 4 kg is generally observed in patients treated with a GLP-1 receptor ago-nist. The reduction in systolic blood pressure ranges from 1 to 7 mm Hg in patients otherwise normotensive. The greatest change in lipid profile is seen on the triglycerides levels with average reductions around 10% to 15%. GLP-1 receptor agonists have also been shown to significantly improve a number of emerging car-diovascular risk markers (lipopro-tein subfractions, anti-inflammatory markers, oxidative stress, endothelial function, etc). Growing evidence sug-gests a significant role for GLP-1 re-ceptor agonists on the cardiovascular

system, such as effects on vascular tone, myocardial contractility, and remodeling. Two clinical studies have focused on the potential cardio-protective effects of GLP-1 receptor agonists on ischemia-reperfusion in-jury.15,16 Although the mechanism in ischemia is unknown, experimental data indicate that the effect is inde-pendent of glycemic control and may involve activation of prosurvival ki-nases (PI3K, Akt, glycogen synthase kinase-3b, p70s6 kinase, ERK1/2 and p38 MAPK).17

PharmacologyIn a Pharmacological Postcondi-

tioning (POSTCON II) trial, investi-gators randomized 387 ST-elevation myocardial infarction (STEMI) patients (with or without diabetes) undergoing percutaneous coronary intervention (PCI), who presented within 12 hours of symptoms and had thrombolysis in myocardial infarction (TIMI) flow grade 0/1 to intravenous exenatide or placebo. The infusion be-gan at least 15 minutes before primary PCI and lasted 6 hours after the proce-dure. At 3 months, cardiac MRI dem-onstrated significantly higher myocar-dial salvage index and reduced infarct

size in both patients with diabetes and patients without diabetes.15

In a similar study, investigators evaluated the effect of a slightly lower dose of exenatide in 71 patients with-out diabetes with STEMI undergoing PCI.16 At 3 months, a trend towards

higher myocardial salvage index was also reported in the exenatide treated group. Several other studies are on-going to better understand the best dose and timing of exenatide infusion to confer the most cardioprotection during reperfusion.

There is no doubt that incretin-based agents offer unique attributes (weight loss/neutrality, limited risk of hypoglycemia, improvement in lipids, and blood pressure) beyond glycemic control, whether this will translate to

Table 1. Effects of Antidiabetics on Glycemic Control and Cardiovascular Biomarkers

Drug FPG PPG Lipids WeightBlood

PressureHypoglycemia Hs-CRP

SFU ↓↓ ↔ ↔ ↑↑ ↔ ↑↑ ↔

TZD ↓↓ ↔ ↓ ↑↑ ↔ ↔ ↓↓

Metformin ↓↓ ↔ ↓ ↔ ↔ ↔ ↓

AGI ↓ ↓↓ ↔ ↔ ↔ ↔ ↓

DPP-4 Inh ↓↓ ↓↓ ↔ ↔ ↓ ↔ ↓

Insulin ↓↓ ↓ ↓↓ ↓ ↔ ↑↑↑ ↔ ↑↑ ↑ ↔

GLP-1 RA ↓↓ ↓ ↓↓ ↓ ↓ ↓↓ ↓↓ ↔ ↓↓

SFU: sulfonylurea, TZD: thiazolidinedione, AGI: alpha-glucosidase inhibitors, DPP-4: dipeptidyl peptidase-4 inhibitor, GLP-1 RA: glucagon-like pep-tide-1 receptor agonist, FPG: fasting plasma glucose, PPG: postprandial plasma glucose, hs-CRP: high-sensitivity C-reactive proteinSource: Ginsberg H, et al. J Cardiovasc Risk. 1999;6(5):337-346; Lehrke M, et al. Rev Diabet Stud. 2011;8(3):382-391.

Growing evidence suggests a significant role for GLP-1 receptor agonists on the cardiovascular system, such as effects on vascular tone, myocardial contractility, and remodeling.

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reduction in cardiovascular morbid-ity and mortality is still unknown. Recently, 2 large random controlled trials partially elucidated the impact of DPP-4 inhibitors on cardiovascular morbidity and mortality.

SAVOR TIMI 53 and EXAMINE Trials

The Saxagliptin Assessment of Vascular Outcomes Recorded in

Patients with Diabetes Mellitus–Thrombolysis in Myocardial In-farction 53 (SAVOR TIMI 53) trial investigators randomized 16,492 patients with T2DM and preexisting cardiovascular disease or multiple cardiovascular risk factors.18 The pa-tients were assigned to either saxa-gliptin or a matching placebo for 2 years. The primary endpoint was a composite of cardiovascular death,

nonfatal MI, or nonfatal ischemic stroke. The secondary endpoint was the primary endpoint plus hospital-ization for heart failure, coronary revascularization, or unstable angi-na. The patients were mostly white obese males with T2DM for about 10 years with a baseline A1C around 8%. Approximately 75% of the pa-tients received aspirin, a statin, and only 50% were on an angiotensin-converting-enzyme inhibitor.

The primary endpoint occurred in 7.3% of patients assigned to saxagliptin compared to 7.2% in the placebo group (HR, 1.0; 95% CI, 0.89 to 1.12). Simi-larly there was no significant difference between the groups for the secondary endpoint (12.8% vs. 12.4% for pla-cebo). More patients in the saxagliptin treated group were hospitalized for heart failure than in the placebo group (3.5% vs. 2.8%, HR, 1.27; 95% CI, 1.07 to 1.51). At the end of the trial, the between group A1C difference was 0.2% (P<0.001 vs. placebo).

The Examination of Cardiovascu-lar Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial investigators randomized 5,380 pa-tients with T2DM and either recent acute MI or unstable angina requiring hospitalization.19 The patient were as-signed to either alogliptin or matching placebo for 18 months. The primary endpoint was similar to the SAVOR trial. The secondary endpoint was the primary endpoint plus urgent revascu-larization due to unstable angina.

The patients were mostly white overweight males with T2DM for about 7 years and a baseline A1C around 8%. More than 90% of the patients were on aspirin and statin. The primary endpoint occurred in 11.3% patients assigned to alogliptin compared to 11.8% in the placebo group (HR, 0.96; P=0.32). Simi-larly, there was no significant dif-ference between the two groups for the secondary endpoint (12.7% vs. 13.4% for placebo, P=0.26). At the

Table 2. Large Cardiovascular Outcome Trials of Incretin-based Therapies

Trial Name/ Drug NPrimary Endpoint

EXAMINE1

Examination of Cardiovascular Outcomes with Alogliptin vs. Standard of Care

5,380 MACE

SAVOR TIMI-532

Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus

16,492 MACE

TECOS3

Trial Evaluating Cardiovascular Outcomes with Sitagliptin

14,000 MACE + unstable angina

CAROLINA4

Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Patients with Type 2 Diabetes

6,000 MACE + unstable angina

LEADER5

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcomes Results - A Long-term Evaluation

9,000 MACE

EXSCEL6

Exenatide Study of Cardiovascular Event Lowering Trial

12,000 MACE

ELIXA7

Evaluation of Cardiovascular Outcomes in Patients with Type 2 Diabetes After Acute Coronary Syndrome During Treatment with Lixisenatide

6,000 MACE + unstable angina

REWIND8

Researching Cardiovascular Events with a Weekly Incretin in Diabetes

9,600 MACE

Source: 1White WB, et al. Am Heart J. 2011;162(4):620-626.2Scirica BM, et al. N Engl J Med. 2013;369(14):1317-1326.3TECOS Study. http://clinicaltrials.gov/show/NCT00790205. Accessed November 18, 2013.4CAROLINA Study. http://clinicaltrials.gov/ct2/show/NCT01243424. Accessed Novermber 18, 2013.5LEADER Study. http://clinicaltrials.gov/ct2/show/NCT01179048? term=LEADER&rank=4. Accessed November 18, 2013.6EXSCEL Study. http://clinicaltrials.gov/ct2/show/NCT01144338? term=EXSCEL&rank=1. Accessed November 18, 2013.7ELIXA Study. http://clinicaltrials.gov/ct2/show/NCT01147250?term=ELIXA&rank=1. Accessed November 18, 2013.8REWIND Study. http://clinicaltrials.gov/ct2/show/NCT01394952?term=REWIND& rank=1. Accessed November 18, 2013.

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end of the trial, the between group difference for A1C was -0.36%.

Because of the small A1C difference between groups, the causal relationship between glucose control and CVD cannot be inferred by these trials. The promising preclinical and retrospective evidence suggesting potential cardio-protective effect of DPP-4 inhibitors in patients with T2DM did not translate in these randomized control trials. Sev-eral caveats should be considered when interpreting the results: (1) the studies were of short duration; (2) patients had diabetes for 7 to 10 years, most likely representing a population with a high atherosclerotic plaque burden; and (3) the 0.7% absolute increased risk in hospitalization for heart failure in the saxaglitin-treated group needs to be confirmed in other trials.

These two large cardiovascular outcome studies provide evidence that saxagliptin and alogliptin used to con-trol glycemia in patients with T2DM do not increase the risk for cardiovas-cular events in an otherwise high-risk population. Several ongoing cardio-vascular safety trials of other incretin-based therapies will provide, in the near future, further evidence to guide clinical practice (Table 2).

CONCLUSIONThere is robust evidence that nor-

malizing glycemia results in reduced risk for kidney disease, blindness, and amputations. The same causal rela-tionship is lacking for cardiovascular disease despite the evidence from epi-demiological and experimental studies. The optimal approach to reduce car-diovascular risk in patients with T2DM remains the well proven strategies of adopting an active healthy eating life-style, maintaining a normal weight, re-ducing blood pressure, lowering LDL-cholesterol, and smoking cessation.

The 2 recent large trials with DPP-4 inhibitors establish the short-term cardiovascular safety of these glucose-lowering agents for patients with T2DM at high risk for cardio-vascular events. Based on clinical trials in acute MI setting, could GLP-1 receptor agonists be the glucose-lowering agents with dual properties that could prevent microvascular and macrovascular disease? Only large randomized control trials will con-firm this assumption.

References1. Emerging Risk Factors Collaboration, et

al. Lancet. 2010;375(9733): 2215-2222.

2. Stark Casagrande S, et al. Diabetes Care. 2013;36(8):2271-2279.

3. Hemmingsen B, et al. Cochrane Data-base Syst Rev. 2011;(6):CD008143.

4. Raz I, et al. Diabetes Care. 2009; 32(3): 381-386.

5. ACCORD Study Group, et al. N Engl J Med. 2010; 362(17):1575-1585.

6. ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358(24):2560-2572.

7. Duckworth W, et al. N Engl J Med. 2009; 360(2):129-139.

8. ORIGIN Trial Investigators, et al. N Engl J Med. 2012;367(4):319-328.

9. Mentlein R. Regul Pept. 1999;85(1):9-24.

10. Amori RE, et al. JAMA. 2007;298(2); 194-206.

11. Russell-Jones D, et al. Diabetes Care. 2012;35(2):252-258.

12. Bergenstal RM, et al. Lancet. 2010; 376(9739):431-439.

13. Eliasson B, et al. Diabetologia. 2012; 55(4):915-25.

14. Wei Y, et al. FEBS Lett. 1995;358(3): 219-224.

15. Bernink FP, et al. Int J Cardiol. 2012; 167(1):289-290.

16. Lønborg J, et al. Eur Heart J. 2012; 33(12):1491-1499.

17. Ban K, et al. Circulation. 2008; 117(18): 2340-2350.

18. Scirica BM, et al. N Engl J Med. 2013; 369(14):1317-1326.

19. White WB, et al. N Engl J Med. 2013; 369(14): 1327-1335.

Full references are available at www.healio.com/endocrinology/education-lab.

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Two large cardiovascular out-come trials of diabetes medi-cations have recently been

completed. These 2 trials provide great insight into dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiovas-cular and overall safety profile. The re-sults of these 2 trials will be discussed and context will be provided to evalu-ate these findings in the broad world of cardiovascular risk reduction.

An extensive amount of preclini-cal data suggested that there might be a cardiovascular benefit to incre-tins. A large meta-analysis of DPP-4 inhibitors suggested lower rates of major adverse cardiac events in rela-tively healthy patients with diabetes. These potential benefits seemed to occur early. This suggested that there may be benefits of DPP-4 inhibi-tion beyond glycemic control due to pleiotropic effects.

As these provocative data were ac-cruing, the Food and Drug Administra-tion (FDA) issued a requirement that all new diabetes drugs provide reassur-ance of their cardiovascular safety if they are to be allowed on the market or to stay on the market. Specifically, the upper bound of the 95% confidence in-terval for the hazard ratio for ischemic events would need to be demonstrated to be less than 1.3. In response to this requirement, several large cardiovas-cular outcome trials were launched.

SAVOR-TIMI 53 TrialThe Saxagliptin Assessment of

Vascular Outcomes Recorded in

Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarc-tion 53 (SAVOR-TIMI 53) trial ran-domized a total of 16,492 patients with type 2 diabetes and either es-tablished cardiovascular disease or multiple cardiovascular risk factors to receive either the DPP-4 inhibi-tor saxagliptin or placebo. The haz-ard ratio (HR) for cardiovascular death, myocardial infarction (MI), or ischemic stroke was 1.00 (95% confidence interval = 0.89 to 1.12, P value for non-inferiority 0.001, P value for superiority = 0.99) (Fig-ure 1).1 Very consistent, the hazard ratio for the more expansive sec-ondary cardiovascular endpoint which, in addition to the primary endpoint, included hospitalization

for unstable angina, heart failure, or revascularization was 1.02 (95% confidence interval = 0.94 to 1.11, P value for non-inferiority 0.001) (Figure 2).1 Unexpectedly and con-trary to the a priori hypothesis, there was an excess in hospitaliza-tion for heart failure. It is important to acknowledge that hospitaliza-tion for heart failure was only one component of a secondary endpoint that was overall neutral. Also, while statistically significant, in absolute terms, the excess rate of hospital-ization for heart failure was only 0.7% over two years, and impor-tantly, there did not appear to be any significant excess in mortality associated with this finding. Sev-eral analyses are ongoing to further

Evaluation of Cardiovascular Effects of Incretin Therapy for Type 2 Diabetes MellitusDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC

Primary endpoint HR for cardiovascular death, MI, or ischemic stroke: 1.00.Source: From Scirica BM, et al. N Engl J Med. 2013;369(14):1317-1326. Reprinted with permission from Massachusetts Medical Society.

Figure 1. Primary Endpoint from SAVOR-TIMI 53

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explore this observation, including detailed analyses of multiple bio-markers, including a b-type natri-uretic peptide (BNP) blood test, that were obtained at baseline and at 2-year followup.

EXAMINE TrialThe Cardiovascular Outcomes

Study of Alogliptin in Subjects With Type 2 Diabetes and Acute Coro-nary Syndrome (EXAMINE) trial randomized 5,380 patients with type 2 diabetes with a recent acute coro-nary syndrome to either the DPP-4 inhibitor alogliptin or placebo. The hazard ratio for the primary end-point of cardiovascular death, myo-cardial infarction, or stroke for alo-gliptin vs. placebo was 0.96 (upper boundary of the one-sided repeated confidence interval = 1.16, P value for non-inferiority 0.001, P value for superiority = 0.32) (Figure 3).2 There was no significant increase in hospitalization for heart failure in the EXAMINE trial, though di-rectionally, there was a similar in-crease as seen in the SAVOR-TIMI 53 trial. As the EXAMINE trial had a little less than one third the number of patients as did the SAVOR-TIMI 53 trial and also a shorter median duration of followup, it is possible that the EXAMINE trial was under-powered to see a significant effect on hospitalization for heart failure. Potentially, the differences could be due to the different drugs stud-ied, though there is no good reason to think one would cause heart fail-ure and the other would not. Much more likely, if the heart failure sig-nal is real, it is a class effect. Alter-natively, the finding of heart failure in the SAVOR-TIMI 53 trial may be spurious and the by-product of mul-tiple comparisons of different safe-ty endpoints. An increase in heart failure has been noted with the use of thiazolidinediones, rosiglitazone, and pioglitazone. Therefore, it is

important to evaluate the potential for incretins to cause heart failure and future studies should carefully adjudicate this outcome.

ComparisonIn the SAVOR-TIMI 53 trial, an

increase in hypoglycemic events was found with saxagliptin vs. placebo. Fortunately, there was no increase in hospitalization for hypoglycemic events. However, in the EXAMINE

trial, no increase in hypoglycemia was reported. It is unlikely that this difference in trial outcomes was due to differences in the drugs. Much more likely, these differences were due to the differing trial populations studied as well as the more sensitive definition of hypoglycemia used in the SAVOR-TIMI 53 trial.

A major concern that had been raised in the endocrinology litera-ture was whether DPP-4 inhibitors

Secondary endpoint HR, including unstable angina, heart failure, or revascularization: 1.02.Source: From Scirica BM, et al. N Engl J Med. 2013;369(14):1317-1326. Reprinted with permission from Massachusetts Medical Society.

Figure 2. Secondary Endpoint from SAVOR-TIMI 53

Primary endpoint HR of cardiovascular death, MI, or stroke: 0.96.Source: From White WB, et al. N Engl J Med. 2013;369(14):1327-1335. Reprinted with permission from Massachusetts Medical Society.

Figure 3. Primary Endpoint from EXAMINE

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increase the risk of pancreatitis and pancreatic cancer. These concerns were based on observational analy-ses and animal data. Reassuringly, neither of these two large random-ized, blinded trials found a signifi-cant difference in pancreatitis or ex-cess in pancreatic (or other) cancers. In fact, in the SAVOR-TIMI 53 trial, a careful prespecified blinded adju-dication process was used to catego-rize pancreatitis and there was no evident signal associated with saxa-gliptin. Furthermore, various safety concerns that have been raised with other classes of diabetes medica-tions (eg, liver failure, fractures) were not noted to be associated with DPP-4 inhibitors in these 2 trials.

Both trials showed that DPP-4 inhibitors significantly improved glycemic control. In the SAVOR-

TIMI 53 trial, the hemoglobin A1C at a 2-year followup was 7.5% in the saxagliptin treated patients and 7.8% in the control patients (P0.001). It is important to realize this reduction was in the context of a significant reduction in the need for add-on dia-betes therapy in the saxagliptin arm vs. placebo arm. Similarly, in the EX-AMINE trial, there was a 0.36% re-duction in hemoglobin A1C for alo-gliptin vs. placebo (P0.001). Thus, both these trials of DPP-4 inhibitors were quite concordant overall, dem-onstrating safe glycemic control.

Neither trial was designed to ex-amine microvascular outcomes that are associated with levels of glyce-mic control. However, the SAVOR-TIMI 53 trial did find that categories of microalbuminuria significantly improved and worsening of micro-albuminuria was significantly less-ened with saxagliptin vs. placebo. Whether this would translate into a reduction in actual progression to renal failure would have required a much longer study.

Why did the prior meta-analyses find a reduction in major adverse cardiovascular events while two large randomized clinical trials did not? Of course, one explanation is that the meta-analyses were spuri-ous and misleading. The very early benefits seen in those analyses were attributed to pleiotropic effects. An alternative explanation is that the very early treatment effects (prior to any potential significant impact on glycemic control) were implausible. Another explanation is that the find-ings were accurate, but only appli-cable to patients with much earlier stages of diabetes and without the additional cardiovascular and medi-cal comorbidities in the higher risk populations tested in the SAVOR-TIMI 53 and EXAMINE trials. The only way to definitively address this uncertainty would be with further large-scale randomized clinical tri-als in patients with diabetes who are much healthier. The practical prob-lem with that approach is the likely low event rates would necessitate a very large and very long study if it is to be adequately powered.

Other TrialsOther large cardiovascular out-

come trials of DPP-4 inhibitors in pa-tients at elevated cardiovascular risk are ongoing. The Sitagliptin Cardio-vascular Outcome Study (TECOS)3 trial which is underway is randomiz-ing patients with diabetes to placebo

or sitagliptin, a very commonly used DPP-4 inhibitor. The TECOS trial will have a longer duration of follow-up than either the SAVOR-TIMI 53 or EXAMINE trials. This may allow a cardiovascular benefit to be seen, if one really does exist and if it was not observed in either the SAVOR-TIMI 53 trial or the EXAMINE trial due to an insufficiently long period of differential glycemic control between the active treatment and placebo arms. Alternatively, any potential safety sig-nal regarding hospitalization for heart failure may also be confirmed (or re-futed) in TECOS.

Additional large-scale trials of DPP-4 inhibitors are also ongoing. The Cardiovascular and Renal Mi-crovascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vas-cular Risk (CARMELINA)4 trial is randomizing patients with diabe-tes to placebo or linagliptin, while the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA)5 trial is randomizing patients with diabetes to glimepiride or linagliptin. With the use of pla-cebo in one trial and with an active control as the comparator in the other trial, these two trials should provide great insight into whether any cardiovascular effects are due to a comparison with placebo or are in-dependent of glycemic effects.

There are also ongoing car-diovascular outcome trials with glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 recep-tor agonists are much more potent inhibitors of DPP-4 than the oral DPP-4 inhibitors. Therefore, any potential cardiovascular benefit (or harm, with respect to the heart fail-ure signals) may be magnified. A number of large randomized clini-cal trials are comparing placebo to GLP-1 receptor agonists: ELIXA6 is testing lixisenatide, EXSCEL7 is

There are other large ongoing

cardiovascular outcome trials

of DPP-4 inhibitors in patients

at elevated cardiovascular

risk that should increase the

understanding of diabetes

medications substantially.

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testing exenatide, LEADER8 is test-ing liraglutide, SUSTAIN9 is testing semaglutide, and REWIND10 is tes-ting dulaglutide. Thus, all together there are thousands of patients be-ing studied in outcome trials of the incretins. Furthermore, there are cardiovascular outcome trials of sodium-glucose cotransporter 2 (SGLT-2) inhibitors ongoing as well. As these trials complete, our understanding of diabetes medica-tions should increase substantially.

References1. Scirica BM, et al. N Engl J Med. 2013;

369(14):1317-1326.

2. White WB, et al. N Engl J Med. 2013;369(14):1327-1335.

3. Sitagliptin Cardiovascular Outcome

Study (MK-0431-082) (TECOS). http://clinicaltrials.gov/show/NCT00790205. Accessed November 18, 2013.

4. Cardiovascular and Renal Microvas-cular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mel-litus at High Vascular Risk (CARME-LINA). http://clinicaltrials.gov/ct2/show/NCT01897532. Accessed November 18, 2013.

5. Cardiovascular Outcome Study of Lina-gliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA). http://clin-icaltrials.gov/ct2/show/NCT01243424. Accessed Novermber 18, 2013.

6. Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide) (ELIXA). http://clinicaltrials.gov/ct2/show/NCT01147250?term=ELIXA&rank=1. Accessed November 18, 2013.

7. Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL). http://clini-

caltrials.gov/ct2/show/NCT01144338? term=EXSCEL&rank=1. Accessed No-vember 18, 2013.

8. Liraglutide Effect and Action in Dia-betes: Evaluation of Cardiovascular Outcome Results - A Long Term Evalu-ation (LEADER). http://clinicaltri-als.gov/ct2/show/NCT01179048? term=LEADER&rank=4. Accessed No-vember 18, 2013.

9. Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Sema-glutide in Subjects With Type 2 Diabetes (SUSTAIN 6). http://clinicaltrials.gov/ct2/show/NCT01720446? term=SUSTAIN+semaglutide&rank=1. Accessed No-vember 18, 2013.

10. Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) http://clinicaltrials.gov/ct2/show/NCT01394952?term=REWIND& rank=1. Accessed November 18, 2013.

Full references are available at www.healio.com/endocrinology/education-lab.

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Reducing CVD Risk in Patients with T2DM: Utilizing Incretin Therapeutics

CASE PRESENTATION

Case 1A 60-year-old man with an 11-year history of type

2 diabetes mellitus (T2DM) and hypertension presents to your office for a second opinion. He is a non-smoker that admits being noncompliant with his diet, but is concerned about his rising A1C and that he is always hungry. BP: 138/98 mm Hg; BMI: 31 kg/m2. He is cur-rently taking: glipizide 5 mg BID, pioglitazone 30 mg OD, simvastatin 20 mg OD, amlodipine 10 mg OD, olmesartan 20 mg OD, and ASA 325 mg OD.

LDL-C: 146 mg/dL

HDL-C: 40 mg/dL

Triglycerides: 314 mg/dL

Non-HDL-C: 219 mg/dL

Total cholesterol: 249 mg/dL

A1C: 8.2%

DISCUSSION This 60-year-old obese hypertensive man with T2DM,

noncompliant with his diet, with metabolic syndrome is

at very high cardiovascular risk, with a low-density lipo-protein cholesterol (LDL-C) goal of 70 mg/dL being a prudent choice given his multiple risk factors. Therapeu-tic lifestyle changes and dietary counseling are needed along with tighter glycemic control, with the addition of a long-acting GLP-1 receptor agonist to reduce his A1C, decrease his weight, reduce his hunger, and have a beneficial effect on postprandial glucose and lipemia. Lipid therapy needs adjusting since simvastatin at 20 mg is clearly not getting him to goal. The substitution of a more potent statin like rosuvastatin 20 mg or atorvastatin 80 mg would bring him closer to his LDL-C goal. An-other option would be switching to atorvastatin 80 mg or 20 mg of rosuvastatin and add ezetimibe or fenofibrate. Data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, support microvascular ben-efits with the addition of fenofibrate to statin therapy, in addition to lowering triglycerides. Evaluation for sleep apnea and weight reduction would also be of significant value in evaluating and treating this patient. Weight re-duction from 5% to 10% through diet and exercise will have a beneficial impact on this patient’s blood pressure, lipids, and A1C.

Case 2A 54-year-old overweight man with type 2 diabetes

mellitus (T2DM) presents to the ER with non-ST segment elevation myocardial infarction (NSTEMI), demonstrat-ing non-specific ST-T wave changes on ECG with CK-MB and troponin T elevations. He smokes 1 pack of ciga-rettes daily. BP: 136/86 mm Hg; BMI: 29 kg/m2; WC: 41 inches. He is currently taking: ASA 81 mg OD, ramipril 10 mg OD, metformin 1000 mg BID, sitagliptin 100 mg OD, glimepiride 2 mg daily, and simvastatin 20 mg OD.

LDL-C: 128 mg/dL

HDL-C: 40 mg/dL

Triglycerides: 195 mg/dL

Non-HDL-C: 167 mg/dL

Total cholesterol: 207 mg/dL

A1C: 7.9%

FBG: 148 mg/dL

DiscussionSeveral factors prominently stand out to indicate

that this patient is at high risk for cardiovascular events. First, his cigarette smoking increases his risk of a sec-ond myocardial infarction since a patient with T2DM is already at very high risk for a major cardiac event. His increased BMI and waist circumference (WC) also in-crease this risk. Not only is obesity now recognized as a disease, but also represents a major modifiable risk fac-tor for cardiovascular disease, second only to cigarette smoking. Excess weight and obesity markedly increase the risk for hypertension, diabetes, coronary artery dis-ease, and congestive heart failure in both men and wom-en as the BMI increases beyond 25 kg/m2.1 The elevated TG/HDL-C ratio of almost 5.0 is not only a marker of insulin resistance and increased risk for MI (which he has already experienced), but also small LDL size, like-ly accompanied by elevated apoB and increased LDL-P. His LDL-C is not optimally controlled at 128 mg/dL. Although new guidelines have not specified treatment

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goals, NCEP-ATP III goals applicable to patients at very high risk, such as this patient, would require an LDL-C <70 mg/dL.

Non-HDL-C has been shown to be a better predictor of risk rather than LDL-C. Optimal non-HDL-C in this patient would be <100 mg/dL (30 mg/dL greater than LDL-C goal). In this patient an additional 45 to 50 mg/dL (35% to 40%) reduction in LDL-C would be required to approach the desired goal. In the Pravastatin or Atorvas-tatin Evaluation and Infection Therapy (PROVE-IT) trial, 80 mg of atorvastatin was effectively utilized in a similar patient population to reduce CV risk. This could provide an additional 20% reduction in LDL-C compared to his present 20 mg dose of simvastatin, while doubling the statin dose would result in only a 6% LDL-C reduction. Rosuvastatin at 20 mg would also provide a similar LDL-C reduction. Despite the use of more potent statins, com-bination therapy should be considered to achieve LDL-C goals. Subset analysis of patients in Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid and Fenofibrate Intervention and Event Lowering in Diabetes

(FIELD) trials have suggested a benefit in patients with mildly elevated triglycerides and decreased HDL-C.

Colesevelam could provide an additional 18% to 25% reduction in LDL-C when added to a statin, while reduc-ing A1C by up to 0.8%. Better glycemic control could be achieved with the subsitution of a glucagon-like peptide-1 (GLP-1) receptor agonist for the dipeptidyl peptidase-4 (DPP-4) inhibitor, which can also decrease weight and improve blood pressure. Enhanced glycemic control will result in better prandial and postprandial lipid regulation.

Not to be overlooked is the value of therapuetic life-style changes in reducing weight, improving glycemic control, and attenuating dyslipidemia with weight re-ductions of 5% to 10% having a significant impact on improving surrogate markers of cardiovascular risk. These lifestyle changes should begin with smoke cessa-tion guidance and counseling, supplemented by diet as well as judicious use of exercise.

Reference1. Sharma AM. Growth Horm IGF Res. 2003;13(Suppl A): S10-S17.

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1. The leading cause of death in patients with T2DM is: A. HyperglycemiaB. Renal FailureC. Electrolyte imbalanceD. Cardiovascular disease

2. A 66-year-old male is being seen in your office for hypertension, dyslipidemia, obesity, and T2DM. His BMI is 29 kg/m2 and A1C is 8.0% and is always hungry. He currently takes a sulfonylurea, metformin, statin, ACE inhibitor, and a thiazide diuretic. He is concerned about his increasing weight and increasing A1C. Which is the best strategy to reduce his A1C, help him lose weight, and reduce his hunger?

A. Add a GLP-1 receptor agonistB. Add bedtime NPH insulinC. Add a long-acting analog insulinD. Add a thiazolidinedione

3. The lifetime risk for cardiovascular events in patients with T2DM is:A. >50%B. 50%C. 40%D. >90%

4. The new American Heart Association/American College of Cardiology (AHA/ACC) 2013 Guidelines recommends high-intensity statin therapy for patients with T2DM, who are?A. >30 years of ageB. >35 years of ageC. >40 years of ageD. Regardless of age

5. GLP-1 receptor agonists appear to have the greatest effects on which of the following?A. Free fatty acid levelsB. HDL-C levelsC. Fasting lipid levelsD. Postprandial lipemia

6. Which of the following best describes GLP-1 receptor agonist therapy on plasma lipids?A. Increases free fatty acidsB. Increases LDL-CC. Increases HDL-CD. Decreases triglycerides

7. In SAVOR-TIMI 53, saxagliptinA. significantly reduced the rate of cardiovascular

death, MI, or stroke.B. significantly increased the rate of cardiovascular

death, MI, or stroke.C. significantly improved glycemic control. D. significantly increased pancreatitis.

8. In EXAMINE, alogliptinA. significantly reduced the rate of cardiovascular

death, MI, or stroke.B. significantly increased the rate of cardiovascular

death, MI, or stroke.C. significantly increased hypoglycemia.D. significantly improved glycemic control.

9. In SAVOR-TIMI 53, saxagliptinA. significantly raised the risk of fractures.B. significantly increased the risk of cancer.C. significantly raised the risk of liver failure.D. significantly raised the risk of hospitalization for

heart failure.

10. In SAVOR-TIMI 53, saxagliptin A. significantly raised the risk of hospitalization for

hypoglycaemia.B. significantly raised the risk of any hypoglycaemia. C. significantly worsened microalbuminuria categories. D. significantly increased severe infections.

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POSTTEST

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Examine more closely the differences, efficacy, and safety of treatment options that target glycemic control. Y N 2 1 Assess the pathophysiology of incretin pathways in type 2 diabetes mellitus. Y N 2 1 Examine approaches to managing the obese patient with type 2 diabetes. Y N 2 1

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